Rhinitis is effectively treated by administration of intranasal corticosteroids (ICSs). The major advantage of ICS administration is that sufficient concentrations of the drug can be directly delivered to the site of action by means of a nasal spray device. Although the therapeutic effect of an ICS is elicited by local action via topical delivery, concerns remain that these agents may reach the systemic circulation in sufficient quantities to produce adverse effects. The regional deposition of corticosteroid droplets in the nasal passages is an important factor to consider when evaluating subsequent pharmacokinetics of nasal sprays for topical or systemic delivery. This proposal will address the development and evaluation of a hybrid computational fluid dynamics- physiologically based pharmacokinetic (CFD-PBPK) model for the distribution and absorption of nasally delivered products to support and facilitate generic drug guidance development, product development, and application review. Three brand-name ICSs with a range of solubilities (Flonase, Veramyst, and Rhinocort Aqua) will be used to study their spray droplet size distribution, localized dose in the nasal passages, and absorption characteristics. CFD methods and CT scan-based sinonasal reconstructions from a subject with normal nasal passages and a subject with rhinitis will be used to simulate and characterize particle deposition delivered by these three corticosteroid nasal sprays. This information will be linked with a PBPK model for localized drug absorption in the nasal mucosa. It is proposed that through the use of CFD simulations of nasal sprays and PBPK model simulations of drug absorption, that accurate estimates of the absorption characteristics of ICSs can be determined to estimate nasal tissue concentrations and blood PK profiles. The specific aims of the proposal are: 1. Characterize the regional distribution patterns in the nasal passages of droplets emitted from three commercial ICSs. Droplet size distributions from each nasal spray product will be determined using laser diffraction. These size distributions will then be used in nasal spray simulations using CFD models of a healthy and rhinitic subject. In each subject, the dose from the nasal spray simulation will be analyzed in anatomical regions of interest. 2. Develop physiologically based absorption models of ICS absorption in the nasal mucosa. Regional dose estimates from the CFD simulations will be linked to PBPK models of the nasal passages to simulate the dissolution, absorption, and mucociliary clearance of ICSs. 3. Characterize the uncertainty and population variability of PBPK model simulations of ICS absorption. Model parameters will be characterized by distributions instead of single parameter values. Monte Carlo simulations will be performed using the PBPK model to characterize differences in nasal tissue and blood concentrations of ICSs resulting from changes in model parameter values.